There is a clinical need for substance abuse medications that are effective against comorbid drug abuse. Addiction to multiple abused substances presents a complex clinical problem, treatment for which may require multiple pharmacological approaches via multiple mechanisms of action. Further, there are several phases of drug addiction in patients (acquisition, withdrawal, craving, relapse) that may not adequately treated by a single mechanism of action of a single drug. Therefore, pharmacotherapies that target dual or multiple mechanisms of complementary pharmacology may provide novel approaches for the effective treatment of drug addiction. A case in point is buprenorphine, a nonselective mu opioid receptor partial agonist/kappa antagonist/nociceptin receptor partial agonist, which is clinically effective against cocaine and heroin addiction, and recently shown to be effective against alcohol abuse as well. Buprenorphine's activity at the nociceptin receptor is thought to play a role in its efficacy in treating cocaine and alcohol addiction. The nociceptin receptor NOP is known to be involved in reward pathways, and nociceptin/Orphanin FQ (N/OFQ), the endogenous agonist for the NOP receptor, has been shown to block self-administration and acquisition of conditioned place preference (CPP) to several drugs of abuse;in particular, morphine, cocaine, amphetamines, and alcohol. A small-molecule NOP agonist has also been shown to block acquisition of morphine and ethanol place preference and reinstatement of drug-seeking. We hypothesize that compounds that target both the NOP receptor and the opioid receptors, and have a desirable mixed profile of NOP agonist/opioid activity, will provide new pharmacotherapeutic approaches for polydrug addiction treatment. Our preliminary data show that a compound with NOP full agonist and mu opioid receptor weak partial agonist activity attentuates acquisition of morphine CPP. We have developed several novel NOP agonists and have extensive structure-activity relationships for NOP affinity and selectivity versus opioid receptors. Using this as a foundation, we propose to design NOP/opioid 'multiple'ligands that have a desired mixed profile of activity as potential agents for drug abuse therapy. Our specific aims are to (i) design novel NOP/opioid mixed ligands with an optimized profile of NOP full agonist activity and selected opioid receptor efficacy, suitable pharmacokinetic properties and blood-brain barrier penetration (ii) to characterize the mixed ligands in vitro for their NOP and opioid affinity and functional profile, evaluate their metabolic stability and determine an overall receptor profile;and (iii) to examine ligands with selected profiles in vivo for their effect on the acquisition of morphine and cocaine CPP, and on drug- and stress-induced reinstatement of morphine and cocaine CPP. We expect that we will identify several novel NOP-opioid mixed ligands with desirable efficacy profiles and suitable drug-like characteristics for further development as pharmacotherapies for the treatment of polydrug addiction. PUBLIC HEALTH RELEVANCE: Addiction to multiple abused substances is quite commonplace among addicts and represents a serious treatment problem and an unmet clinical need. Development of pharmacotherapies that have multiple targeted mechanisms of action in a single agent can provide a single new treatment option for the various aspects of the addiction process and/or for patients addicted to multiple drugs. The discovery of bifunctional NOP/opioid receptor ligands, as proposed in this application, offers the advantage of combining dual-targeted activities of known complementary pharmacology and broad anti-addictive effects, into single agents that can be developed as pharmacotherapies for polydrug addiction.